2. Academic Validation
  3. SETDB1 promotes mammalian liver regeneration by stimulating cytokine CSF3 in hepatocytes

SETDB1 promotes mammalian liver regeneration by stimulating cytokine CSF3 in hepatocytes

  • Cell Rep. 2025 Jun 24;44(6):115843. doi: 10.1016/j.celrep.2025.115843.
Xiao-Yan Huang 1,  Dong Yang 1,  Yin-Zhe Liu 1,  En-Xiang Zhang 1,  Qiao Yang 2,  Wang Kang 1,  Xiao-Ou Zhang 3,  Junwei Shi 4,  Chun-Qing Song 5
Affiliations

Affiliations

  • 1 Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang 310024, China; Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang 310024, China.
  • 2 Department of Infectious Diseases, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, China.
  • 3 Shanghai Key Laboratory of Maternal and Fetal Medicine, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
  • 4 Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 5 Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang 310024, China; Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang 310024, China. Electronic address: songchunqing@westlake.edu.cn.
PMID: 40531618 DOI: 10.1016/j.celrep.2025.115843
Abstract

Discovering mechanisms of regeneration holds great promise for advancing regenerative medicine. Non-histone modifications by epigenetic factors participate in important biological processes. Through in vivo CRISPR screening combined with partial hepatectomy (PHx-CRISPR), we identified the histone H3K9 methyltransferase SETDB1 as an enhancer of regeneration. Loss of SETDB1 delays regeneration, and overexpressing SETDB1 accelerates liver regeneration across various liver injury models. SETDB1 promotes liver regeneration by positively regulating the expression of granulocyte colony-stimulating factor (CSF3) in hepatocytes. SETDB1 facilitates the expression of CSF3 in hepatocytes by methylating and activating Akt, establishing CSF3 as a critical downstream effector in the SETDB1-AKT liver regeneration pathway. Notably, increasing SETDB1 levels in humanized mouse liver suppresses drug-induced liver damage. Our findings reveal an unexpected role for non-histone modification by SETDB1 in regulating cytokine signaling during liver regeneration and offer insights into targeted therapies for regenerative medicine and tissue repair.

Keywords

Akt methylation; CP: Stem cell research; CSF3/CSF3r; PHx-CRISPR screening; SETDB1; Tyosinemia type I mice; acute liver injury; hepatectomy; liver regeneration; liver-humanized mouse; non-histone methylation.

Figures
Products
Inhibitors & Agonists
Other Products